LAG3 Binding Peptides

ABSTRACT

This disclosure provides peptides that bind to LAG3 and can be used to block its interaction with other molecules such as MHC-II, FGL1, and α-synuclein. These peptides, with their demonstrated activity and short half-life, can be used to activate cellular immunity while significantly reducing the potential for adverse events that is often associated with the antibody-based checkpoint inhibitors. The peptides can be used as stand-alone therapeutics or can be used as immune modulators in combination with other therapies.

This application incorporates by reference the contents of a 3.72 kbtext filed created on Jul. 20, 2020 and named“00047900277sequencelisting,” which is the sequence listing for thisapplication.

Each scientific reference, patent, and published patent applicationcited in this disclosure is incorporated herein by reference in itsentirety.

TECHNICAL FIELD

This disclosure relates generally to immunomodulatory peptides.

BACKGROUND

Lymphocyte activation gene 3 (LAG3, also known as LAG-3, LAG 3, Lag3,CD223, FDC protein) is a member of the immunoglobulin superfamily ofreceptors.

LAG3 is expressed on immune cells (activated T cells, Huard et al.,1994; natural killer cells, Triebel et al., 1990; B cells, Kisielow etal., 2005; plasmacytoid dendritic cells, Workman et al., 2009), where itbinds to MHC class II (MHC-II) and serves as an immune checkpointreceptor. LAG3 also binds to fibrinogen-like protein (FGL1), anddisrupting this binding can potentiate anti-tumor immunity (Wang et al.,2019). There is a continuing need for useful modulators of immunecheckpoint pathways.

LAG3 is also expressed on neurons, where it serves as a receptor for theα-synuclein aggregates characteristic of synucleinopathies (Mao et al.,2016). Synucleinopathies are disorders characterized by the abnormalaccumulation of aggregates of α-synuclein protein in neurons, nervefibers, or glial cells. Synucleinopathies include idiopathic andinherited forms of Parkinson's disease (PD); Diffuse Lewy Body (DLB)disease, also known as Dementia with Lewy Bodies or Lewy body dementia;incidental Lewy body disease; Lewy body variant of Alzheimer's disease(LBV); Combined Alzheimer's and Parkinson disease (CAPD); pure autonomicfailure (PAF); multiple system atrophy (MSA), such asolivopontocerebellar atrophy, striatonigral degeneration, and Shy-DragerSyndrome; pantothenate kinase-associated neurodegeneration; Down'sSyndrome; Gaucher disease-related synucleinopathies; andneurodegeneration with brain iron accumulation. There is a continuingneed for therapeutic agents for treating or managing symptoms ofsynucleinopathies.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows the results of fluorescent resonance energy transfer (FRET)assays.

DETAILED DESCRIPTION

This disclosure provides peptides that bind to LAG3 and can be used toblock its interaction with other molecules such as MHC-II, FGL1, andα-synuclein. The amino acid sequences of these peptides are shown inTable 1, below.

TABLE 1 Peptide Sequences peptide amino acid sequence SEQ ID NO:   6ITMWGYDTDEDDNLVIYLTD  1  11 RERGGDDFAQDDYYVTIFYR  2  16QGSTSGWGFGAMYELTYDVY  3  41 TVDADGDLYFDMEEGVLVFM  4  62LAGHYHYLTAGSQDIYEYND  5  68 EDKAPWWQLDMEFEFRLDRV  6  69AEFDHFDVGQTLDIASWDSY  7 115 RTDRYTLSYIWTSDEWMLFD  8 141GGVAIFLALFGGMVSSWEWD  9 146 VFRMDWDEKEVRLYADDILL 10 154EHNREQVLEVMYSFQVNDYF 11 155 SLPYSNIYIELDSGYWNSES 12

These peptides, with their demonstrated activity and short half-life,can be used to activate cellular immunity while significantly reducingthe potential for adverse events that is often associated with theantibody-based checkpoint inhibitors. The peptides can be used asstand-alone therapeutics or can be used as immune modulators incombination with other therapies. They can be genetically encoded, forexample, within CAR T and oncolytic viral platforms to effectivelytarget the tumor microenvironment.

In some embodiments, a disclosed peptide is modified using chemical orrecombinant methods to enhance its stability or other pharmacokineticproperties. See, e.g., US 2017/0020956. Modifications include, but arenot limited to, replacement of one or more L-amino acid with itscorresponding D-form, acetylation on a C- and/or N-terminal residue,amidation on a C- and/or N-terminal residue, cyclization,esterification, glycosylation, acylation, attachment of myristic orpalmitic acid, addition of an N-terminal glycine, addition of lipophilicmoieties such as long fatty acid chains, and PEGylation.

Peptides can be made by any method known in the art, including syntheticmethods, recombinant methods, or both. Synthetic methods includesolid-phase and solution methods, and may include the use of protectivegroups. See, e.g., Bodanszky et al. (1976), McOmie (1973), Merrifield(1963), Neurath et al. (1976), Stuart & Young (1984).

Recombinant production of peptides can be carried out using anynucleotide sequence(s) encoding the peptides in any suitable expressionsystem. Nucleic acid molecules encoding one or more of the disclosedpeptides can be incorporated into an expression cassette that includescontrol elements operably linked to the coding sequences. Controlelements include, but are not limited to, initiators, promoters(including inducible, repressible, and constitutive promoters),enhancers, and polyadenylation signals. Signal sequences can beincluded. The expression cassette can be provided in a vector that canbe introduced into an appropriate host cell for production of thepeptide(s). Methods of constructing expression cassettes and expressionvectors are well known. Expression vectors can include one or moreexpression cassettes encoding one or more peptides comprising,consisting essentially or, or consisting of any of SEQ ID NOS:1-7.

In some embodiments, one or more peptides are expressed as a componentof a fusion protein. Other components of the fusion protein can be, forexample, a cytokine or an engineered T cell receptor (TCR). A fusionprotein can comprise one or more linkers between its components. In someembodiments, a linker between a peptide and another component of thefusion protein can comprise a proteolytic cleavage site to release thepeptide after expression of the fusion protein. See, e.g., US2016/0138066; US 2018/0135060; US 2014/0343251; US 2012/0142891;Rodriguez et al., 2014.

In some embodiments, a component of a fusion protein is a moiety, suchas albumin or transthyretin, which can enhance the plasma half-life ofthe peptide. In other embodiments, a peptide or a modified version of apeptide is conjugated to the moiety. Methods of preparing suchconjugates are well known in the art (e.g., Penchala et al., 2015;Kontermann, 2016; Zorzi et al., 2017).

In some embodiments, a component of a fusion protein is a partnermolecule, such as a peptide or protein such as an antibody intended toincrease the half-life of a peptide or modified peptide in vivo and/orto provide specific delivery to a target tissue or cell. Alternatively,a peptide or modified version thereof can be conjugated to the partnermolecule. Conjugation may be direct or can be via a linker. In some ofthese embodiments, a peptide or a modified version thereof can bealtered to substitute one or more amino acids with amino acids used toattach partner molecules, such as lysine, or by N-terminal extension ofthe peptide with, e.g., 1, 2, 3, or 4 glycine spacer molecules.

This disclosure also provides CAR-T cells that express one or more ofthe disclosed peptides. Methods of preparing CAR-T cells are disclosed,for example, in U.S. Pat. Nos. 9,328,156; 9,845,362; and 9,101,584.

This disclosure also provides oncolytic viruses containing a nucleicacid molecule encoding one or more of the disclosed peptides. See US2017/0157188; Lawler et al., 2017; US 2015/0250837. Oncolytic virusesinclude, but are not limited to, reovirus, Seneca Valley virus,vesicular stomatitis virus, Newcastle disease virus, herpes simplexvirus, morbillivirus virus, retrovirus, influenza virus, Sindbis virus,poxvirus, and adenovirus.

Examples of oncolytic reovirus include REOLYSIN® (pelareorep) andreoviruses disclosed in US 2017/0049829.

Examples of oncolytic Seneca Valley virus include NTX-101 (Rudin et al.,2011).

Examples of oncolytic vesicular stomatitis virus are disclosed in Stojdlet al., 2000; and Stojdl et al., 2003.

Examples of oncolytic Newcastle disease virus include 73-T PV701 andHDV-HUJ strains (see also Phuangsab et al., 2001; Lorence et al., 2007;and Freeman et al., 2006).

Examples of oncolytic herpes simplex virus include NV1020 (Geevargheseet al., 2010) and T-VEC (Andtbacka et al., 2013).

Examples of oncolytic morbillivirus virus include oncolytic measlesviruses such as MV-Edm (McDonald et al., 2006) and HMWMAA (Kaufmann etal., 2013).

Examples of oncolytic retrovirus are disclosed in Lu et al., 2012.

Examples of oncolytic influenza virus are disclosed, for example, in US2018/0057594.

Examples of oncolytic Sindbis virus are disclosed, for example, inLundstrom, 2017.

Examples of oncolytic poxvirus are disclosed, for example, in Chan &McFadden, 2014.

Examples of oncolytic adenovirus include ONYX-015 (Khuri et al., 2000)and H101 or Oncorine (Liang, 2018).

Therapeutic Uses

The peptides and modified versions thereof disclosed herein have anumber of therapeutic applications, including treatinghyperproliferative disorders (e.g., cancer). “Treat,” as used herein,includes reducing or inhibiting the progression of one or more symptomsof the condition for which a peptide or modified version thereof isadministered. The peptides and modified versions thereof may also beuseful for reducing one or more symptoms of or for treatingsynucleopathies, infectious diseases, and sepsis and for enhancing aresponse to vaccination.

“Administer” as used herein includes administration of a disclosedpeptide or modified version thereof itself as well as administration byvarious vehicles described below.

In some embodiments, one or more of the disclosed peptides and/ormodified versions thereof, are directly administered. In some of theseembodiments, a peptide carrier system is used. A number of peptidecarrier systems are known in the art, including microparticles,polymeric nanoparticles, liposomes, solid lipid nanoparticles,hydrophilic mucoadhesive polymers, thiolated polymers, polymer matrices,nanoemulsions, and hydrogels. See Patel et al. (2014), Bruno et al.(2013), Feridooni et al. (2016). Any suitable system can be used.

In some embodiments, an engineered T cell that expresses and secretesone or more disclosed peptides can be used to deliver LAG3 inhibition atthe site of engagement of the T cell receptor with an antigen. The Tcell-based therapy can be, for example, a CAR-T cell that expresses oneor more of the disclosed peptides. Either inducible or constitutiveexpression can be used.

In some embodiments, an oncolytic virus can be used to deliver one ormore of the disclosed peptides. Either inducible or constitutiveexpression can be used.

In other embodiments one or more of the disclosed peptides are deliveredusing one or more nucleic acids encoding the peptide(s) (e.g., DNA,cDNA, PNA, RNA or a combination thereof); see, e.g., US 2017/0165335.Nucleic acids encoding one or more peptides can be delivered using avariety of delivery systems known in the art. Nucleic acid deliverysystems include, but are not limited to, gene-gun; cationic lipids andcationic polymers; encapsulation in liposomes, microparticles, ormicrocapsules; electroporation; virus-based, and bacterial-baseddelivery systems. Virus-based systems include, but are not limited to,modified viruses such as adenovirus, adeno-associated virus, herpesvirus, retroviruses, vaccinia virus, or hybrid viruses containingelements of one or more viruses. US 2002/0111323 describes use of “nakedDNA,” i.e., a “non-infectious, non-immunogenic, non-integrating DNAsequence,” free from “transfection-facilitating proteins, viralparticles, liposomal formulations, charged lipids and calcium phosphateprecipitating agents,” to administer a peptide. Bacterial-based deliverysystems are disclosed, e.g., in Van Dessel et al. (2015) and Yang et al.(2007).

In some embodiments, a peptide is administered via an RNA moleculeencoding the peptide. In some embodiments, the RNA molecule isencapsulated in a nanoparticle. In some embodiments, the nanoparticlecomprises a cationic polymer (e.g., poly-L-lysine, polyamidoamine,polyethyleneimine, chitosan, poly(β-amino esters). In some embodiments,the nanoparticle comprises a cationic lipid or an ionizable lipid. Insome embodiments, the RNA molecule is conjugated to a bioactive ligand(e.g., N-acetylgalactosamine (GalNAc), cholesterol, vitamin E,antibodies, cell-penetrating peptides). See, e.g., Akinc et al. (2008),Akinc et al. (2009), Anderson et al. (2003), Behr (1997), Boussif et al.(1995), Chen et al. (2012), Dahlman et al. (2014), Desigaux et al.(2007), Dong et al. (2014), Dosta et al. (2015), Fenton et al. (2016),Guo et al. (2012), Howard et al. (2006), Kaczmarek et al. (2016),Kanasty et al. (2013), Kauffman et al. (2015), Kozielski et al. (2013),Leus et al. (2014), Lorenz et al. (2004), Love et al. (2010), Lynn &Langer (2000), Moschos et al. (2007), Nair et al. (2014), Nishina et al.(2008), Pack et al. (2005), Rehman et al. (2013), Schroeder et al.(2010), Tsutsumi et al. (2007), Tzeng et al. (2012), Won et al. (2009),Xia et al. (2009), Yu et al. (2016).

In some embodiments, an RNA molecule can be modified to reduce itschances of degradation or recognition by the immune system. The ribosesugar, the phosphate linkage, and/or individual bases can be modified.See, e.g., Behlke (2008), Bramsen (2009), Chiu (2003), Judge &MacLachlan (2008), Kauffman (2016), Li (2016), Morrissey (2005), Prakash(2005), Pratt & MacRae (2009), Sahin (2014), Soutschek (2004), Wittrup &Lieberman (2015). In some embodiments, the modification is one or moreof a ribo-difluorotoluyl nucleotide, a 4′-thio modified RNA, aboranophosphate linkage, a phosphorothioate linkage, a 2′-O-methyl(2′-OMe) sugar substitution, a 2′-fluoro (2′-F), a 2′-O-methoxyethyl(2′-MOE) sugar substitution, a locked nucleic acid (LNA), and an L-RNA.

In some embodiments, administration is carried out in conjunction withone or more other therapies. “In conjunction with” includesadministration together with, before, or after administration of the oneor more other therapies.

Pharmaceutical Compositions, Routes of Administration, and Devices

One or more peptides, modified peptides, nucleic acid molecules, CAR-Tcells, and/or oncolytic viruses, as discussed above, are typicallyadministered in a pharmaceutical composition comprising apharmaceutically acceptable vehicle. The “pharmaceutically acceptablevehicle” may comprise one or more substances which do not affect thebiological activity of the peptides or modified versions thereof and,when administered to a patient, does not cause an adverse reaction.Pharmaceutical compositions may be liquid or may be lyophilized.Lyophilized compositions may be provided in a kit with a suitableliquid, typically water for injection (WFI) for use in reconstitutingthe composition. Other suitable forms of pharmaceutical compositionsinclude suspensions, emulsions, and tablets.

Pharmaceutical compositions can be administered by any suitable route,including, but not limited to, intravenous, intramuscular, intradermal,intraperitoneal, subcutaneous, epidural, intratumoral, transdermal(e.g., US 2017/0281672), mucosal (e.g., intranasal or oral), pulmonary,and topical (e.g., US 2017/0274010) routes. See, e.g., US 2017/0101474.

Administration can be systemic or local. In addition to local infusionsand injections, implants can be used to achieve a local administration.Examples of suitable materials include, but are not limited to,sialastic membranes, polymers, fibrous matrices, and collagen matrices.

Topical administration can be by way of a cream, ointment, lotion,transdermal patch (such as a microneedle patch), or other suitable formswell known in the art.

Administration can also be by controlled release, for example, using amicroneedle patch, pump and/or suitable polymeric materials. Examples ofsuitable materials include, but are not limited to, poly(2-hydroxy ethylmethacrylate), poly(methyl methacrylate), poly(acrylic acid),poly(ethylene-co-vinyl acetate), poly(methacrylic acid), polyglycolides(PLG), polyanhydrides, poly(N-vinyl pyrrolidone), poly(vinyl alcohol),polyacrylamide, poly(ethylene glycol), polylactides (PLA),poly(lactide-co-glycolides) (PLGA), and polyorthoesters.

Devices comprising any of the peptides, modified peptides, nucleic acidmolecules, CAR-T cells, and/or oncolytic viruses described aboveinclude, but are not limited to, syringes, pumps, transdermal patches,spray devices, vaginal rings, and pessaries.

Treatment of Hyperproliferative Disorders, Including Cancer

In some embodiments, one or more of the peptides, modified peptides,nucleic acid molecules, CAR-T cells, and/or oncolytic viruses describedabove are administered to a patient to inhibit the progression of ahyperproliferative disorder, including cancer. Such inhibition mayinclude, for example, reducing proliferation of neoplastic orpre-neoplastic cells; destroying neoplastic or pre-neoplastic cells; andinhibiting metastasis or decreasing the size of a tumor.

Examples of cancers include, but are not limited to, melanoma (includingcutaneous or intraocular malignant melanoma), renal cancer, prostatecancer, breast cancer, colon cancer, lung cancer, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, uterinecancer, ovarian cancer, rectal cancer, cancer of the anal region,stomach cancer, testicular cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin'slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, lymphocyticlymphoma, cancer of the bladder, cancer of the kidney or ureter,carcinoma of the renal pelvis, neoplasm of the central nervous system(CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor,brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoidcancer, squamous cell cancer, and T-cell lymphoma.

Combination Cancer Therapies

In some embodiments, one or more of the peptides, modified peptides,nucleic acid molecules, CAR-T cells, and/or oncolytic viruses describedabove are administered in conjunction with one or more other cancertherapies or immunotherapies, such as those described below.

In some embodiments, the second therapy comprises a second agent thatreduces or blocks the activity of PD-1 (e.g., nivolumab, pembrolizumab,durvalumab) or CTLA-4 (e.g., ipilimumab, tremelimumab).

In some embodiments, the second therapy comprises an agent that reducesor blocks the activity of PD-L1 (e.g., atezolizumab).

In some embodiments, the second therapy comprises an agent that reducesor blocks the activity of LAG3 or other inhibitory checkpoint moleculesand/or molecules that suppress the immune system. These moleculesinclude, but are not limited to:

-   -   1. V-domain Immunoglobulin Suppressor of T cell Activation        (VISTA, also known as c10orf54, PD-1H, DD1α, Gi24, Dies1, and        SISP1; see US 2017/0334990, US 2017/0112929, Gao et al., 2017,        Wang et al., 2011; Liu et al., 2015);    -   2. T-cell Immunoglobulin domain and Mucin domain 3 (TIM-3; see        US 2017/0198041, US 2017/0029485, US 2014/0348842, Sakuishi et        al., 2010);    -   3. killer immunoglobulin-like receptors (KIRs; see US        2015/0290316);    -   4. agents that inhibit indoleamine (2,3)-dioxygenase (IDO; see        Mellemgaard et al., 2017);    -   5. B and T Lymphocyte Attenuator (BTLA; see US 2016/09222114);        and    -   6. A2A adenosine receptor (A2AR; see Beavis et al., 2015; US        2013/0267515; US 2017/0166878; Leone et al., 2015;        Mediavilla-Varela et al., 2017; Young et al., 2016).

Agents that reduce or block the activity of LAG3 include, but are notlimited to, BMS-986016, IMP321, and GSK2831781 (He et al., 2016).

Agents that reduce or block the activity of VISTA include, but are notlimited to, small molecules, such as CA-170, and antibodies (e.g., LeMercier et al., 2014).

Agents that reduce or block the activity of TIM-3 include, but are notlimited to, antibodies such as MBG453 and TSR-022; see Dempke et al.,2017.

Agents that reduce or block the activity of KIRs include, but are notlimited to, monoclonal antibodies such as IPH2101 and Lirilumab(BMS-986015, formerly IPH2102); see Benson & Caligiuri, 2014.

Agents that reduce or block the activity of IDO include, but are notlimited to, epacadostat and agents disclosed in US 2017/0037125.

Agents that reduce or block the activity of BTLA include, but are notlimited to, peptides (e.g., Spodzieja et al., 2017).

Agents that reduce or block the activity of A2AR include, but are notlimited to, small molecules such as CPI-444 and vipadenant.

In some embodiments, the second therapy comprises a cytokine (e.g.,interleukin 7).

In some embodiments, the second therapy comprises an agonist of astimulatory checkpoint molecule. These molecules include, but are notlimited to:

-   -   1. CD40;    -   2. OX40;    -   3. glucocorticoid-induced tumor necrosis factor-related protein        (GITR); and    -   4. Inducible T-cell COStimulator (ICOS).

Agonists of CD40 include, but are not limited to, CD40 agonistmonoclonal antibodies such as cp-870,893, ChiLob7/4, dacetuzumab, andlucatumumab. See, e.g., Vonderheide et al., 2007; Khubchandani et al.,2009; Johnson et al., 2010; Bensinger et al., 2012; Vonderheide andGlennie, 2013; Johnson et al., 2015.

Agonists of OX40 include, but are not limited to, OX40 agonistantibodies such as MOXR0916, MED16469, MED10562, PF-045618600,GSK3174998, and INCCAGN01949, and OX40L-Fc fusion proteins, such asMEDI6383. See, e.g., Huseni et al., 2014; Linch et al., 2015;Messenheimer et al., 2017. See also Shrimali et al., 2017.

Agonists of GITR include, but are not limited to, MEDI1873. See, e.g.,Schaer et al., 2012; Tigue et al., 2017.

Agonists of ICOS include, but are not limited to, ICOS agonistantibodies JTX-2011 and GSK3359609. See, e.g., Harvey et al., 2015;Michaelson et al., 2016.

In other embodiments, the second therapy comprises a 4-1BB agonist(Shindo et al., 2015), such as urelumab; a 4-1BB antagonist (see US2017/0174773); an inhibitor of anaplastic lymphoma kinase (ALK; Wang etal., 2014; US 2017/0274074), such as crizotinib, ceritinib, alectinib,PF-06463922, NVP-TAE684, AP26113, TSR-011, X-396, CEP-37440, RXDX-101;an inhibitor of histone deacetylase (HDAC; see US 2017/0327582); a VEGFRinhibitor, such as axitinib, sunitinib, sorafenib, tivozanib,bevacizumab; and/or an anti-CD27 antibody, such as varlilumab.

In some embodiments, the second therapy comprises a cancer vaccine(e.g., Duraiswamy et al., 2013). A “cancer vaccine” is an immunogeniccomposition intended to elicit an immune response against a particularantigen in the individual to which the cancer vaccine is administered. Acancer vaccine typically contains a tumor antigen which is able toinduce or stimulate an immune response against the tumor antigen. A“tumor antigen” is an antigen that is present on the surface of a targettumor. A tumor antigen may be a molecule which is not expressed by anon-tumor cell or may be, for example, an altered version of a moleculeexpressed by a non-tumor cell (e.g., a protein that is misfolded,truncated, or otherwise mutated).

In some embodiments, the second therapy comprises a chimeric antigenreceptor (CAR) T cell therapy. See, e.g., John et al., 2013; Chong etal., 2016.

In some embodiments, one or more of the peptides, modified peptides,nucleic acid molecules, CAR-T cells, and/or oncolytic viruses describedabove are administered in conjunction with a CAR-T cell cancer therapyto increase the efficacy of the CAR-T cell cancer therapy.

In some embodiments, one or more of the peptides, modified peptides,nucleic acid molecules, CAR-T cells, and/or oncolytic viruses describedabove are administered in conjunction with an oncolytic virus asdisclosed, for example, in US 2017/0143780. Non-limiting examples ofoncolytic viruses are described above.

Treatment of Synucleinopathies

In some embodiments, one or more of the peptides, modified peptides,nucleic acid molecules, CAR-T cells, and/or oncolytic viruses describedabove may be useful to reduce a symptom of a synucleinopathy, eitheralone or in combination with other therapeutic interventions such asL-DOPA, dopamine agonists (e.g., ropinirole, pramipexole), dopaminereuptake inhibitors (e.g., amantadine), and cholinesterase inhibitors(e.g., donepezil, rivastigmine, galantamine). Examples ofsynucleinopathies include idiopathic and inherited forms of Parkinson'sdisease (PD); Diffuse Lewy Body (DLB) disease, also known as Dementiawith Lewy Bodies or Lewy body dementia; incidental Lewy body disease;Lewy body variant of Alzheimer's disease (LBV); Combined Alzheimer's andParkinson disease (CAPD); pure autonomic failure (PAF); multiple systematrophy (MSA), such as olivopontocerebellar atrophy, striatonigraldegeneration, and Shy-Drager Syndrome; pantothenate kinase-associatedneurodegeneration; Down's Syndrome; Gaucher disease-relatedsynucleinopathies; and neurodegeneration with brain iron accumulation.

Treatment of Sepsis

LAGS expression is up-regulated in sepsis (Patil et al., 2017).Accordingly, one or more of the peptides, modified peptides, or nucleicacids described above may be useful to treat sepsis, either alone or incombination with other therapeutic interventions such as antibiotics,intravenous fluids, and vasopressors.

Treatment of Infectious Diseases

In some embodiments, one or more of the disclosed peptides, modifiedpeptides, or nucleic acids described above can be administered to treatinfectious diseases, including chronic infections, caused, e.g., byviruses, fungi, bacteria, and protozoa, and helminths, either alone orin combination with other therapeutic interventions.

Examples of viral agents include human immunodeficiency virus (HIV),Epstein Barr Virus (EBV), Herpes simplex (HSV, including HSV1 and HSV2),Human Papillomavirus (HPV), Varicella zoster (VSV) Cytomegalovirus(CMV), and hepatitis A, B, and C viruses.

Examples of fungal agents include Aspergillus, Candida, Coccidioides,Cryptococcus, and Histoplasma capsulatum.

Examples of bacterial agents include Streptococcal bacteria (e.g.,pyogenes, agalactiae, pneumoniae), Chlamydia pneumoniae, Listeriamonocytogenes, and Mycobacterium tuberculosis.

Examples of protozoa include Sarcodina (e.g., Entamoeba), Mastigophora(e.g., Giardia), Ciliophora (e.g., Balantidium), and Sporozoa (e.g.,Plasmodium falciparum, Cryptosporidium).

Examples of helminths include Platyhelminths (e.g., trematodes,cestodes), Acanthocephalins, and Nematodes.

Use as Vaccine Adjuvants

In some embodiments one or more of the disclosed peptides, modifiedpeptides, or nucleic acids described above can be administered as avaccine adjuvant in conjunction with a vaccine to enhance a response tovaccination (e.g., by increasing effector T cells and/or reducing T cellexhaustion). The vaccine can be, for example, an RNA vaccine (e.g., US2016/0130345, US 2017/0182150), a DNA vaccine, a recombinant vector, aprotein vaccine, or a peptide vaccine. Such vaccines can be delivered,for example, using virus-like particles, as is well known in the art.

Example 1. Peptide Disruption of LAG3-MHC-II Interaction

A Homogeneous Time-resolved Fluorescence (HTRF) LAG3/MHC-II bindingassay (Cisbio US Inc.) was used to measure the interaction betweenMHC-II and LAG3 in the presence of peptides 11, 16, 62, 68, 115, 141,146, and 155. In this assay, the interaction between Tag1-LAG3 andTag2-MHC-II is detected by using anti-Tag1-Terbium (HTRF donor) andanti-Tag2-XL665 (HTRF acceptor). When the donor and acceptor antibodiesare brought into close proximity due to LAG3 and MHC-II binding,excitation of the donor antibody triggers fluorescent resonance energytransfer (FRET) towards the acceptor antibody, which in turn emitsspecifically at 665 nm. This specific signal is directly proportional tothe extent of LAG3/MHC-II interaction. Thus, an agent that blocks theinteraction between LAG3 and MHC-II will cause a reduction in HTRFratio.

Tag1-LAG3 protein (10 nM), Tag2-MHCII protein (20 nM), and peptides(3-fold dilutions beginning with 100 μM) were combined and incubated for15 minutes. Anti-Tag1-Tb and anti-Tag2-XL665 antibodies were added andincubated for one hour, then simultaneous measurement of both 620 nMcryptate and 665 nm acceptor emissions were read. Peptide LG11(SAPWEPLHWPEDWWQGTGEW; SEQ ID NO:13) served as a positive peptidecontrol. Peptide 93 (RVPAPVKEQVQKQYPNAGAI; SEQ ID NO:15) served as anegative or low activating peptide control. An anti-human LAG3 antibody(Novoprotein #GMP-A092, Lot 0331158) served as an antibody positivecontrol. The results are shown in FIG. 1, and the determined IC₅₀ valuesare shown in Table 2, below.

TABLE 2 Peptide Disruption of LAG3-MHC-II Interaction IC₅₀ in LAG3:MHCIIPeptide ID TR-FRET Assay, μM 11 0.353 16 0.220 62 0.308 68 2.940 1150.154 141 6.690 146 0.199 155 0.130 Anti-LAG3 mAb 0.001 LG11 18.4 LowActivity Peptide 63

Example 2. Peptide Disruption of LAG3-FGL1 Interaction

This example tested the ability of peptides to inhibit the interactionbetween human LAG3 and FGL1. The peptides were tested using a HumanLAG3/FGL1 TR-FRET Binding Assay (BPS Bioscience) carried out accordingto the manufacturer's instructions.

Peptides 6, 41, 68, 69, 115, 146, 154, and 155 were tested at 100, 33,and 11 μM. Peptide LG56 (HIQNWSYWLNQDMMNQQVWKS; SEQ ID NO:14) served asa peptide positive control. Peptide 93 (SEQ ID NO:15) served as anegative or low activating peptide control. A neutralizing anti-humanLAG3 antibody (BPS Bioscience Cat. #71219) was used as an antibodypositive control.

Reaction mixes were incubated 1 hr at RT before development. Afterdevelopment, plate was read in a Tecan M1000 TR-FRET instrument. Theresults are shown in FIG. 1, and the determined IC₅₀ values are shown inTable 3, below.

TABLE 3 Peptide Disruption of LAG3-FGL1 Interaction IC₅₀ in LAG3:FLG1Peptide ID TR-FRET Assay, μM 6 2.60 41 9.20 68 ~21 69 3.30 115 9.10 1467.20 154 7.20 Anti-LAG3 mAb 0.02 LG56 14.0 Low Activity Peptide >100

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1. A peptide comprising an amino acid sequence selected from the groupconsisting of SEQ ID NO:1, SEQ ID NO:4, and SEQ ID NO:9.
 2. Apharmaceutical composition, comprising: (a) a peptide selected from thegroup consisting of peptide 6 (SEQ ID NO:1), peptide 11 (SEQ ID NO:2),peptide 16 (SEQ ID NO:3), peptide 41 (SEQ ID NO:4), peptide 62 (SEQ IDNO:5), peptide 68 (SEQ ID NO:6), peptide 69 (SEQ ID NO:7), peptide 115(SEQ ID NO:8), peptide 141 (SEQ ID NO:9), peptide 146 (SEQ ID NO:10),peptide 154 (SEQ ID NO:11), and peptide 155 (SEQ ID NO:12); and (b) apharmaceutically acceptable vehicle.
 3. A method of inhibiting theprogression of a hyperproliferative disorder, inhibiting the progressionof a synucleinopathy, inhibiting the progression of sepsis, inhibitingthe progression of an infectious disease, or enhancing a response to avaccine, comprising administering to an individual in need thereof aneffective amount of a peptide selected from the group consisting ofpeptide 6 (SEQ ID NO:1), peptide 11 (SEQ ID NO:2), peptide 16 (SEQ IDNO:3), peptide 41 (SEQ ID NO:4), peptide 62 (SEQ ID NO:5), peptide 68(SEQ ID NO:6), peptide 69 (SEQ ID NO:7), peptide 115 (SEQ ID NO:8),peptide 141 (SEQ ID NO:9), peptide 146 (SEQ ID NO:10), peptide 154 (SEQID NO:11), and peptide 155 (SEQ ID NO:12).
 4. The method of claim 3,wherein the peptide is administered to inhibit progression of thehyperproliferative disorder.
 5. The method of claim 3, wherein thehyperproliferative disorder is a cancer.
 6. The method of claim 4,wherein the cancer is a melanoma.
 7. The method of claim 3, furthercomprising administering a second therapy.
 8. The method of claim 6,wherein the second therapy is selected from the group consisting of: (i)a cancer vaccine; (ii) a chimeric antigen receptor (CAR) T cell therapy;(iii) a therapy that comprises reducing or blocking activity of amolecule selected from the group consisting of PD-1, PD-L1,lymphocyte-activation gene-3 (LAG3), cytotoxic T-lymphocyte-associatedantigen 4 (CTLA-4), V-domain Immunoglobulin Suppressor of T cellActivation (VISTA), T-cell Immunoglobulin domain and Mucin domain 3(TIM-3), a killer immunoglobulin-like receptor (KIR), indoleamine(2,3)-dioxygenase (IDO), B and T Lymphocyte Attenuator (BTLA), A2Aadenosine receptor (A2AR); (iv) a cytokine; (v) an agonist of a moleculeselected from the group consisting of CD40, OX40, glucocorticoid-inducedtumor necrosis factor-related protein (GITR), and Inducible T-cellCOStimulator (ICOS); (vi) an oncolytic virus; and (vii) a therapeuticagent selected from the group consisting of a 4-1BB agonist, a 4-1BBantagonist, an inhibitor of anaplastic lymphoma kinase (ALK), aninhibitor of histone deacetylase (HDAC), and an inhibitor of VEGFR. 9.The method of claim 3, wherein the peptide is selected from the groupconsisting of peptides peptide 11 (SEQ ID NO:2), peptide 16 (SEQ IDNO:3), peptide 62 (SEQ ID NO:5), peptide 68 (SEQ ID NO:6), peptide 115(SEQ ID NO:8), peptide 141 (SEQ ID NO:9), peptide 146 (SEQ ID NO:10),and peptide 155 (SEQ ID NO:12).
 10. The method of claim 3, wherein thepeptide is administered to inhibit the progression of a synucleinopathy.11. The method of claim 10, wherein the synucleinopathy is selected fromthe group consisting of Parkinson's disease (PD), dementia with Lewybodies (DLB), pure autonomic failure (PAF), and multiple system atrophy(MSA).
 12. The method of claim 10, wherein the peptide is selected fromthe group consisting of peptide 6 (SEQ ID NO:1), peptide 41 (SEQ IDNO:4), peptide 68 (SEQ ID NO:6), peptide 115 (SEQ ID NO:8), peptide 146(SEQ ID NO:10), peptide 154 (SEQ ID NO:11), and peptide 155 (SEQ IDNO:12).
 13. The method of claim 3, wherein the peptide is administeredto inhibit the progression of sepsis.
 14. The method of claim 3, whereinthe peptide is administered to inhibit the progression of an infectiousdisease.
 15. The method of claim 3, wherein the peptide is administeredto enhance a response to a vaccine.
 16. The method of claim 3, whereinthe peptide is selected from the group consisting of peptide 68 (SEQ IDNO:6), peptide 115 (SEQ ID NO:8), peptide 146 (SEQ ID NO:10), peptide155 (SEQ ID NO:12).